Psychostimulant agent

ABSTRACT

The present invention relates to a pharmaceutical composition comprising as active ingredient a compound of the Formula I ##STR1## wherein R 1  stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkyl comprising 3 to 8 carbon atoms; 
     R 2  stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; alkyl comprising 1 to 8 carbon atoms substituted by halogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3 to 8 carbon atoms, 
     with the proviso that groups R 1  and R 2  together contain at least three carbon atoms. The invention also relates to a process for the preparation of compounds of the Formula I by methods known per se. The compounds of the Formula I are phychostimulants having a new spectrum of effect which can be used in therapy for increasing psychical activity (learning and retention) and for treating clinical patterns of depression and deficiencies of learning and retention like in Alzheimer&#39;s disease, and are void of side effects (e.g. due to catecholamine release) of known stimulants.

This is a continuation of co-pending application Ser. No. 07/269,665filed on 15 Jul. 1988, now abandoned.

CROSS REFERENCE TO RELATED APPLICATION

This application is a National Phase Application of PCT HU 87/00040,filed 25 Sep. 1987 and based upon Hungarian National Application 4101/86of 25 Sep. 1986 under the International Convention.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions stimulating thecentral nervous system and having a new spectrum of activity, newphenylakylamine derivatives which can be used as active ingredient insuch pharmaceutical compositions, a process for the preparation of thesuch active ingredients and pharmaceutical compositions and the use ofthe new phenylalkylamine derivatives and pharmaceutical compositionscomprising the same for stimulating the central nervous system.

The pharmaceutical compositions of the present invention exhibit theiractivity in the organism mainly by inhibiting the neuronal uptake ofbiogenic amines.

BACKGROUND OF THE INVENTION

It is known that the most important dose-dependent effect of theso-called indirectly acting sympathomimetic amines belonging chemicallyto the class of phenylakylamines (e.g. the endogenous phenyl ethylamine(PEA) and tyramine) resides in the release of catecholamines--especiallynoradrenaline from the plasma stores of the neurons. Othernon-endogenous phenylakylamines (e.g. amphetamine and metamphetamine)possess similar properties. Moreover, the noradrenaline releasing effectand depending on the dose the effects of other transmitter amines (e.g.serotonin) is strong and long lasting for metabolic reasons.Metamphetamine, also inhibits the neuronal uptake of indirectly actingendogenous sympathomimetic amines to a significant extent, but thiseffect is completely suppressed by noradrenaline release under in vivoconditions.

DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that in the class ofphenyl alkylamines a suitable modification of the chemical structure cancompletely eliminate the known characteristic and dominant effect ofthis compound group namely the effect of inducing the outflow oftransmitter amines and can strengthen a hitherto subordinated effect ofthis compound group namely the inhibition of neuronal uptake ofsympathomimetic amines, in a selective manner. Thus stimulants having anew spectrum of activity can be obtained.

According to the present invention there are provided biologicallyactive phenyl alkylamines of the Formula I, salts thereof, processes forthe preparation of the compounds, pharmaceutical compositions comprisingas active ingredient the said compounds or salts thereof and the use ofthe compounds or pharmaceutical compositions comprising the same.##STR2##

In the present specification the substituent definitions of the Formulaeis as follows:

R¹ stands for straight or branched chain alkyl comprising 1 to 8 carbonatoms; phenylakyl having 7 to 10 carbon atoms; phenyl; or cycloalkylcomprising 3 to 8 carbon atoms;

R² stands for straight or branched chain alkyl comprising 1 to 8 carbonatoms; alkyl comprising 1 to 8 carbon atoms substituted by halogen,hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenylgroups; phenyl; or cycloalkyl having 3 to 8 carbon atoms,

so that groups R¹ and R² together contain at least three carbon atoms;

R³ stands for straight or branched chain alkyl comprising 2 to 8 carbonatoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkylcomprising 3 to 8 carbon atoms; and

R⁴ stands for straight or branched chain alkyl comprising 1 to 8 carbonatoms; alkyl having 1 to 8 carbon atoms substituted by halogen, hydroxy,alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups;phenyl; or cycloalkyl having 3 to 8 carbon atoms;

so that R³ and R⁴ together contain at least 5 carbon atoms; but when R³stands for methyl, R⁴ is other than benzyl; and further so that if R³stands for ethyl, R⁴ is other than isobutyl.

A and B stand for groups which are capable of forming a --NH--R² groupwhen reacting with each other or comprise this latter group and;

X stands for halogen or a sulfonic acid ester group.

The present invention comprises a process for the preparation ofcompounds of the Formula I and salts thereof which comprises reacting acompound of the Formula II ##STR3## with a compound of the Formula IIIB--R² (in which Formulae R¹ and R² are as stated above and A and B standfor groups which are either capable of forming a --NH--R² group whenreacting with each other or comprise the said group) and thereafter ifdesired converting the compound of the Formula I into a salt formed withan organic or inorganic acid and/or liberating a compound of the FormulaI from a salt and if desired finishing a compound of the Formula I or asalt thereof in the form of a pharmaceutical composition by methodsknown per se.

Thus the compounds of the Formula I can be prepared by reacting a ketoneof the Formula IV ##STR4## with an amine of the Formula V H₂ N--R² andreducing the ketimine intermediate formed without or after isolation.The reduction can be carried out by methods known per se, e.g. bycatalytic hydrogenation (preferably in the presence of a palladium orRaney-nickel catalyst) or by using a complex metal hydride (e.g. sodiumborohydride) or with the aid of a conventional chemical reducing agent(e.g. sodium dithionite or amalgamated aluminum).

According to a further realization of the process of the presentinvention a compound of the Formula VII ##STR5## is reacted with analkylating agent of the Formula VI, ##STR6## or an amine of the FormulaV is alkylated with a compound of the Formula VIII. ##STR7## The saidreactions can preferably be carried out in the presence of an acidbinding agent. For this purpose an excess of the amine starting materialmay serve or an organic or inorganic base (e.g. triethylamine orpotassium carbonate) or a basic ion-exchanging resin can be used.

The compounds of Formula XI ##STR8## can be prepared by methylating acompound of the Formula VII by reacting the same with formaldehyde andformic acid.

Th compounds of the Formula I prepared by the process of the presentinvention are in the free base form lipoid-soluble oily substances whichcan be--if desired--converted into crystalline water-soluble salts. Saltformation can be carried out by using pharmaceutically acceptableinorganic or organic acids (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid,maleic acid etc). The compounds of the Formula I can be liberated fromthe acid addition salts by conventional methods. The compounds of theFormula I and biologically acceptable acid addition salts thereof can beused as active ingredients in the preparation of human pharmaceuticalcomposition.

According to a further aspect of the present invention there areprovided pharmaceutical compositions comprising as active ingredient atleast one compound of the Formula I or a pharmaceutically acceptableacid addition salt thereof.

A particularly desirable compound is the compound of Formula XII##STR9## where R⁵ is alkyl having 2-4 carbon atoms.

According to a still further aspect of the present invention there isprovided a process for the preparation of pharmaceutical compositionswhich comprises admixing a compound of the Formula I or apharmaceutically acceptable acid addition salt thereof with suitableinert pharmaceutical carriers.

The pharmaceutical compositions can be prepared by known methods of thepharmaceutical industry. The active ingredient can be finished in theconventional dosage forms (e.g. tablets, pills, coated pills, dragees,capsules, injections etc). The pharmaceutical compositions can comprisethe usual carriers, additives, sliding agents, fillers, auxiliary agentsetc.

The compounds of the Formula I significantly inhibit thetyramine-induced noradrenaline release from the plasma pores of neuronsby inhibiting the tyramine uptake. As opposed to known phenylalkylamines the compounds of the Formula I do not exhibit anoradrenaline releasing effect. At the same time the compounds of theFormula I strongly inhibit the neuronal uptake of noradrenaline andcopamine, considerably increase the catecholaminergic activity,but--contrary to amphetamine and methamphetamine--do not influenceserotonergic activity even if administered at high doses.

The compounds of the Formula I are stimulants of the central nervoussystem which show a stimulating effect in learning and antidepressivepharmacological tests, increase motility and metabolism only to amoderate extent, exert no considerable anorectic effect and are butslightly toxic.

Contrary to a main group of known psychoenergetic agents, the compoundsof the Formula I are devoid of MAO inhibiting activity andare--concerning their mechanism of activity and chemicalstructure--considerably different from known tricyclic antidepressantstoo.

It can be declared on the basis of the aforesaid that the phenylalkylamines of the Formula I constitute a psychopharmacone group of anew mechanism of effect, being suitable for increasing physical activity(learning, memory storing) and for the medical treatment of clinicalpatterns of depression as well as diseases with significant learning andmemory deficits likes Alzheimer's disease, presumably without exhibitingthe side-effects of known stimulants which cause catecholamine release.

According to a still further aspect of the present invention there isprovided a method of treatment which comprises treating healthy or illhumans with a pharmaceutical composition containing an effective amountof a compound of the Formula I or a pharmaceutically acceptable acidaddition salt thereof.

The preferred daily dose amounts of from about 10 mg to about 150 mg,particularly to about 30 mg. The pharmaceutical compositions may beadministered preferably orally, parenterally or by the sublingual route.

Due to their low toxicity the compounds of the Formula I can also beused in pediatrics, in a suitable trans-calculated dose.

The suitable veterinary dose amounts to 2-8 mg/kg.

The compounds of the Formula IX form a sub-group of the compounds of theFormula I being new and never disclosed in the prior art.

SPECIFIC EXAMPLES

Examples without limiting the scope of protection to the Examples.

Chemical examples EXAMPLE 1

To a solution of 16.2 g (0.1 mole) of benzyl-propyl-ketone in 200 ml ofmethanol 23.6 g (0.4 mole) of isopropyl amine and 6 g of a 5%palladium/charcoal catalyst are added and the reaction mixture ishydrogenated under a pressure of 7-10 atm. under shaking. After theuptake of the calculated amount of hydrogen the reaction mixture isfiltered, the filtrate is evaporated and the residue dissolved inethanol comprising hydrochloric acid. The mixture is evaporated. Theresidual N-iso-propyl-1-phenyl-2-pentylamine-hydrochloride can bepurified by recrystallization. Mp.: 136°-139° C.

EXAMPLE 2

To a solution of 16.2 g (0.1 mole) of benzyl-propyl-ketone in 30 ml ofmethanol a solution of 7.5 g (0.1 mole) of 3-propanol-amine and 20 ml ofmethanol is added. The mixture is allowed to stand, whereupon 1.9 g ofsodium borohydride are added, the reaction mixture is allowed again tostand and then evaporated. The residue is taken up in water, extractedwith benzene, the benzene solution is dried and evaporated. The residualcruse N-(3-hydroxypropyl)-1-phenyl-2-pentylamine is purified bydistillation in vacuo. Bp.: 100°-110° C./0.5 Hgmm, n²⁰ _(D) =1.5173.

An etheral solution of the above base is acidified to pH 2 by adding anetheral oxalic acid solution. The precipitated oxalate is filtered anddried. Mp.: 144°-146° C. (ethyl-acetate).

EXAMPLE 3

To a solution of 19.62 g (0.1 mole) of deoxybenzoine in 130 ml methanol7.8 g (0.13 mole) of n-propyl-amine and after standing for some hours3.78 g (0.1 mole) of sodium borohydride are added. The reaction mixtureis allowed to stand and thereafter evaporated. The residue is taken upin water and extracted with benzene. The benzene solution is acidifiedwith 10% hydrochloic acid under stirring. The precipitated crystallineN-propyl-1,2-diphenyl-ethylamine-hydrochloride is filtered and dried.Mp.: 229°-231° C. (ethanol-ether).

EXAMPLE 4

11.0 g (0.068 mole) of benzyl-propyl-ketone are dissolved in 110 ml ofbenzene, whereupon 8.0 g (0.135 mole) of n-propyl-amine and 22.6 g (0.2mole) of anhydrous calcium chloride are added to the solution. Thereaction mixture is stirred at 40°-50° C. for 6 hours, then filtered andevaporated. The crude ketimine thus obtained is dissolved in 120 ml ofmethanol, whereupon 6.4 g (0.17 mole) of sodium borohydride are added.The reaction mixture is allowed to stand, whereupon it is poured into500 ml of water and extracted five times with 100 ml of benzene each.The benzene solution is dried and evaporated. The crudeN-propyl-1-phenyl-2-pentylamine thus obtained is purified bydistillation in vacuo. B.p.: 112°-120° C./7 Hgmm, n²⁰ _(D) =1.5030.

The ethyl acetate solution of the above base is acidified by addingethanol containing hydrochloric acid. The precipitated hydrochloride ispurified and dried. Mp.: 122°-124° C. (ethanol-ether).

EXAMPLE 5

To a solution of 21.03 g (0.1 mole(of 1,3-diphenyl-acetone in 140 ml of96% ethanol 11.8 g (0.2 mole) of n-propylamine are added, the mixture isstirred for an hour, whereupon 3.5 g of amalgamated aluminum foils areadded. The reaction mixture is stirred at 55° C. for 20 hours, filteredand evaporated. The residue is dissolved in benzene and acidified understirring with 10% hydrochloric acid. The precipitated crystallineN-propyl-1,3-diphenyl-2-propylamine-hydrochloride is filtered and dried.Mp.: 174°-176° C. (ethanol-ether).

EXAMPLE 6

To a solution of 29.6 g (0.2 mole) of benzyl-ether-ketone in 200 ml of96% ethanol 34 ml (0.5 mole) of propyl amine are added, the mixture isstirred for an hour, whereupon 6.75 g of amalgamated aluminium foils areadded. The reaction mixture is stirred at 55° C. for 5 hours, whereupon60 ml of a 40% sodium hydroxide solution are added under stirring. Themixture is filtered and the filtrate is evaporated. The residue is takenup in benzene, washed with water and extracted with 150 ml of 10%hydroxhloric acid. The acidic solution is made alkaline with a 40%sodium hydroxide solution, extracted with benzene, the benzene solutionis dried and evaporated. The residual N-propyl-1-phenyl-2-butyl-amine ispurified by distillation in vacuo. Bp.: 84°-88° C./0.5 Hgmm, n²⁰ _(D)=1.4956.

The above base is dissolved in ether and the solution is acidified byadding ethanol containing hydrochloric acid. The precipitatedcrystalline hydrochloride is filtered and dried, mp.: 98°-100° C.(ethyl-acetate).

EXAMPLE 7

To a solution of 67.5 g (0.5 mole) of 1-phenyl-2-propyl-amine in 340 mlof benzene 17.0 g (0.074 mole) of 2-methoxyethyltosylate (J. Org. Chem.9, 235 1944) are added. The reaction mixture is heated to boiling for 3hours, and evaporated. The residue is taken up in benzene, extractedwith 100 ml of a 10% sodium hydroxide solution and washed with 700 ml ofwater. The benzene phase is dried and evaporated. The residual crudeN-(2-methoxyethyl)-1-phenyl-2-propyl-amine is purified by distillationin vacuo. B.p.: 94°-102° C./8 Hgmm, n²⁰ _(D) =1.5012.

The etheral solution of the above base is acidified with ethanolcontaining hydrochloric acid. The precipitated crystalline hydrochlorideis filtered and dried. M.p.: 115°-118° C. (acetone).

EXAMPLES 8-14

The following compounds enumerated in Table 1 are prepared in ananalogous manner to Examples 1-7.

                                      TABLE 1                                     __________________________________________________________________________                                  Acid used                                       Example            B.p.       for salt                                                                              M.p. Recryst.                           No.  R.sup.1                                                                           R.sup.2   °C./Hgmm                                                                      n.sub.D.sup.20                                                                    transformation                                                                        °C.                                                                         solvent                            __________________________________________________________________________     8   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5      HCl     145-147                                                                            ethanol-ether                       9   C.sub.2 H.sub.5                                                                   C.sub.6 H.sub.11                                                                        137-140/1                                                                            1,5160                                                                            HCl     202-203                                                                            acetone-ethanol                    10   C.sub.3 H.sub.7                                                                   CH.sub.3   47-50/15                                                                            1,4203                                                                            HCl     125.5                                                                              ethanol-ether                      11   C.sub.4 H.sub.9                                                                   C.sub.3 H.sub.7                                                                           --   --  HCl     78-80                                                                              ethyl-acetate                      12   C.sub.4 H.sub.9                                                                   CH(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                      --   --  HCl     174-176                                                                            ethyl-acetate                      13   C.sub.6 H.sub.13                                                                  C.sub.3 H.sub.7                                                                         118-126/0,2                                                                          --  (COOH).sub.2                                                                          118-120                                                                             .sub.- i-propanol                 14   CH.sub.3                                                                          (CH.sub.2).sub.2 Br                                                                       --   --  HBr     148-150                                                                            acetonitrile                       __________________________________________________________________________

In the following Examples the preparation of pharmaceutical compositionscomprising as active ingredient a compound of the Formula I or IX,respectively, is described. As active ingredient the product of Example4 is used, but any other compound of the Formula I or IX may be appliedas well.

EXAMPLE 15

Hard gelatine capsules having the following composition are prepared:

    ______________________________________                                        Component         Amount, mg/capsule                                          ______________________________________                                        N-propyl-1-phenyl-2-pentyl-                                                                     30.0                                                        amine-hydrochloride                                                           Maize starch      67.0                                                        Avicel            50.0                                                        Lactose           50.0                                                        Polyvinyl pyrrolidone                                                                           1.0                                                         Talc              2.0                                                         Total weight      200.0                                                       ______________________________________                                    

The capsules are prepared as follows (for 1000 capsules)

30.0 g of the active ingredient are homogenized with 67.0 g of maizestarch, 50 g of Avicel and 50 g of lactose. The homogeneous powdermixture is granulated with an alcoholic polyvinyl pyrrolidone solutionon a sieve No. 18, dried and re-granulated on a sieve No. 24. Afterre-granulation the talc is added and the granules thus obtained arefilled into "Snap fit No. 1" capsules either manually or on a machine.The capsules are made free of dust, polished and packed.

EXAMPLE 16

Suppositories having the following composition are prepared:

    ______________________________________                                        Component        Amount, mg/suppository                                       ______________________________________                                        N-propyl-1-phenyl-2-                                                                           25.0                                                         pentylamine-hydrochloride                                                     Massa Estarinum ® C (1)                                                                    2975.0                                                       Total weight     3000.0                                                       ______________________________________                                         (1) = Adeps solidus hartfett DAB (Dynamit Nobel)                         

The suppositories are prepared as follows (for 1000 suppositories):

2975 g of Massa Estarinum® C are weighed in a duplicator adjusted to39°-40° C. and melt. To the melt suppository mass 25 g of the activeingredient are added and stirred until it is completely dissolved (about5-10 minutes). From the melt suppositories weighing 3.0 g are casted.After cooling the excess of the suppository mass is removed. Theready-for-use suppositories are removed from the form and packed.

EXAMPLE 17

Dragees (coated pills) having the following composition are prepared:

    ______________________________________                                        Component         Amount mg/dragee core                                       ______________________________________                                        N-propyl-1-phenyl-2-                                                                            30                                                          pentylamine-hydrochloride                                                     Maize starch      51                                                          Lactose           82                                                          Luviscol VA64      4                                                          Stearin            4                                                          Avicel            25                                                          Talc               4                                                          Total weight:     200                                                         ______________________________________                                    

The dragee core is prepared as follows:

The active ingredient, the maize starch and the lactose are homogenized(mixture I). The Luviscol and stearin are dissolved in isopropanol(solution II).

The homogeneous powder mixture (I) is granulated with the isopropanolsolution (II). The granules are dried and re-granulated on a sieve No.16. The Avicel and talc are added and homogenized. Dragee cores areprepared by using a convex die having a diameter of 10 mm. The drageecore thus obtained can be coated with a syrup or film layer byconventional methods (e.g. E. Pandula, G. Takacs. Industrial Pharmacy(Ipari Gyogyszerezet), Medicina, Budapest (1964); H. A. Lieberman, L.Lachmann: Pharmaceutical dosage forms, Marcel Dekkar, Inc. N.Y. (1982))

EXAMPLE 18

Tablets having the following composition are prepared:

    ______________________________________                                        Component         Amount, mg/tablet                                           ______________________________________                                        N-propyl-1-phenyl-2-                                                                            30                                                          pentylamine-hydrochloride                                                     Maize starch      29                                                          Lactose           24                                                          Maize starch      9                                                           Gelatine alba     3                                                           Talc              3                                                           Magnesium stearate                                                                              2                                                           Total weight:     100                                                         ______________________________________                                    

The tablets are prepared as follows:

The active ingredient, maize starch and lactose are sieved andhomogenized, whereupon the mixture is granulated with an about 5%aqueous gelatine solution. The granules are dried to a moisture contentof 2% and re-granulated on a sieve No. 18. To the granules as externalphase the remaining part of maize starch, talc and magnesium stearateare added and from the mixture tablets are pressed by using a die havinga diameter of 8 mm.

EXAMPLE 19

Ampoules having the following composition are prepared:

    ______________________________________                                        Component           Amount                                                    ______________________________________                                        N-propyl-1-pheny-2- 30.0 mg                                                   pentylamine-hydrochloride                                                     Sodium chloride      8.9 mg                                                   Ammonium hydroxide  q.s                                                       solution 1.7%                                                                 Distilled water per injection                                                                     ad 1.00 ml                                                ______________________________________                                    

The ampouls are prepared as follows (for 1000 ampouls).

30.0 g of the active ingredient and 8.9 g of sodium chloride aredissolved in 800 ml of distilled water suitable for injection purposes.The pH of the solution is adjusted to 3.0-8.0 by adding a 1.7% ammoniumhydroxide solution. The solution is filled up to 1000.0 ml withdistilled water suitable for injection purposes. The microorganismcontent of the solution is decreased by means of bacterial filtrationbefore filling to ampouls and sterilization.

The filtered solution is immediately filled into suitable ampoules whichare then sealed. The ampouls are sterilized. Further manufacture iscarried out by conventional methods of the pharmaceutical industry.

II. BIOLOGICAL EXAMPLES II/1. Determination of noradrenaline releasingeffect in cats (in vivo)

The condition of the nicitating membrane of an anesthetized cat iscontinuously registered by the aid of an auxotonic writing leverkymograph. Releases of noradrenaline induce contractions of the thenictitating membrane in a dose-dependent manner. The i.p. administrationPEA induces contractions of the nictitating membrane which is transientin nature. Amphetamine and methamphetamine, however, cause contractionof long duration. In the above test the compounds of the Formula I donot cause any contraction. (Method: J. Knoll: Monoamine Oxidase and ItsInhibition (Eds Wolstenholme and Knight), Elsevier, 1976, page 131).

II/2. Determination of psychostimulant effect in rats

a) Modified jumping test (J. Knoll and B. Knoll: Arch. Int. Pharmacody.148, 200 (1964).

In this test small doses of amphetamine (up to 1-2 mg/kg) improve whilelarger doses of amphetamine (above 3 mg/kg) deteriorate learning andretention in a dose-dependent manner. The compounds of the Formula Igive rise to an improvement of performance at a dose of 0.5-15 mg/kg ina dose-dependent manner. Thus the new compounds are devoid of theperformance deteriorating effect characteristic of high doses ofamphetamine due to an activation of the serotonergic system (doses above10 mg/kg are considered to be very high).

b) Shuttle-box text

(Method: B. Knoll, J. Knoll: Pol. J. Pharmacol. Pharm. 34, 17-23 1982)

According to this test the daily administration of 1 mg/kg s.c. dose ofamphetamine significantly increases the acquizition of a conditionedreaction and its retention during the five days of observation. Theincrease of performance is however accompanied by a disproportionatelyhigh intersignal reaction. The effect of higher amphetamine doses (5-10mg/kg) can not be even evaluated in the shuttle-box because of anextremely high general motility increasing effect.

The daily administration of 0.5 mg/kg of the compound according toExample 4 gives rise to a significant increase of performance over thecontrol without signs of increased general motility.

Compound according to Example 4 increased learning and retentions fromthe very first day during the complete test-period, even whenadministered in an extreme high daily dose of 15 mg/kg. Whereas theperformance of these animals is unusually efficient, the increase of theintersignal reactions can be deemed as moderate, when taking intoconsideration the extremely high performance. Animals treated with adose of 15 mg/kg of the compound according to Example 4 completelymaintain the performance acquired at the end of the one-week learningperiod even for 6 weeks after the termination of the treatment.According to the tests the compounds of the present invention bringabout an extremely high learning performance increasing effect, the saideffect being very strong and broad but corresponding to an othermechanism than the activity of amphetamine.

II/3 Determination of antagonism of tetrabenzine-induced depression, inlearning test, on rats

a) Jumping test

Method: J. Knoll, B. Knoll: Arzneimittel Forschung 8, 339 (1958), 9, 633(1959).

The solid conditioned reflex acquired on the jumping test can not beinhibited even with high doses of the compounds of the Formula I (e.g.with a dose of 15 mg/kg of compound according to Example 6). The reflexcan be completely inhibited only with high doses of tetrabenazine (5mg/kg) while the depressive effect of tetrabenazine can be entirelyantagonized by a dose of 15 mg/kg of the compound according to Example6.

b) Shuttle-box test

Method: B. Knoll, J. Knoll: Pol. J. Pharmacol. Pharm. 34, 17-23 (1982).

According to this test depression caused by tetrabenazine can beantagonized by the compounds of the Formula I. In Table 3 the numericalvalues of the series of test carried out by using the compound accordingto Example 6 are disclosed.

Similar results are obtained when using the compounds according toExamples 4 and 14.

                  TABLE 3                                                         ______________________________________                                        C = control (physiological sodium chloride solution, s.c., daily,             N = 12);                                                                      T = 0.5 mg/kg of tetrabenazine, s.c., daily N = 12;                           V = 0.5 mg/kg of tetrabenazine + 10 mg/kg of compound                         according to Example 7, s.c., daily, N = 12.                                         Response to stimulus                                                   Learning     F+        f+      f-      IR                                     ______________________________________                                        1st day                                                                              C     29.67     51.67   18.67   9.25                                                ±6.31  ±6.62                                                                              ±7.96                                                                              ±2.39                                      T     9.58      31.25   59.17   10.25                                               ±3.74  ±9.20                                                                              ±11.68                                                                             ±2.45                                      V     34.60     49.80   16.40   10.50                                               ±7.00  ±7.08                                                                              ±10.18                                                                             ±2.05                               2nd day                                                                              C     53.33     25.25   21.42   11.00                                               ±9.87  ±6.01                                                                              ±10.84                                                                             ±2.51                                      T     8.50      30.75   60.75   8.33                                                ±3.68  ±9.81                                                                              ±11.81                                                                             ±2.34                                      V     62.20     21.00   16.80   14.70                                               ±11.39 ±7.17                                                                              ±11.45                                                                             ±5.27                               3rd day                                                                              C     58.25     31.17   10.58   13.83                                               ±10.43 ±8.35                                                                              ±6.46                                                                              ±4.00                                      T     11.42     15.83   72.75   4.67                                                ±4.94  ±6.14                                                                              ±11.10                                                                             ±1.23                                      V     69.20     9.80    21.00   21.30                                               ±11.65 ±3.17                                                                              ±12.51                                                                             ±7.50                               4th day                                                                              C     66.00     28.83   5.17    13.25                                               ±8.97  ±8.14                                                                              ±4.09                                                                              ±5.80                                      T     9.8       17.83   73.08   4.50                                                ±4.02  ±6.81                                                                              ±10.63                                                                             ±1.31                                      V     64.90     17.70   17.40   14.30                                               ±10.92 ±5.21                                                                              ±11.66                                                                             ±5.06                               5th day                                                                              C     72.25     23.33   4.52    12.83                                               ±7.60  ±6.62                                                                              ±3.60                                                                              ±4.06                                      T     17.67     12.58   69.75   6.92                                                ±8.10  ±4.03                                                                              ±11.64                                                                             ±1.90                                      V     76.10     8.50    15.40   16.80                                               ±11.29 ±2.33                                                                              ±10.31                                                                             ±5.78                               ______________________________________                                         F+ = % of animals showing a conditioned reaction                              f+ = % of animals responding to unconditioned stimulus,                       f- = % of animals which do not respond even to unconditioned stimulus,        IR = number of intersignal reactions.                                    

II/4. Determination of effect exerted on motility, on rats

The test is carried out in a Shuttle-box without introducing current andlight. The number of spontaneous passings over from side of the box tothe other is registered and summarized by the apparatus for anobservation period of 30 minutes. The test is carried out on groupscomprising 112 CFY rats of both sexes weighing 180-200 each. The testcompound of the Formula I is added prior to the test subcutaneously,together with tetrabenzine and desmethyl-imipramine (DMI) referencecompounds, respectively.

According to this test the compounds of Examples 3 and 6 do not increasemotility in a dose of 10 mg/kg, while compounds of Examples 4, 5 and 11do increase motility in the same dose. The motility inhibiting effect of1 mg/kg of tetrabenazine is significantly antagonized by a 2.5 mg/kgdose of compound of Example 6 and completely antagonized already by a 1mg/kg dose of compound of Example 4. In this test, DMI is inhibitory byitself rather than antagonistic against tetrabenzaine induced depressionof motility.

II/5. Determination of the effect exerted on metabolism, in rats

Method: B. Issekutz, B. Issekutz, Jr.: Naumyn. Schiedeberg 2 ArchPharmac 306 (1942).

In this test the compounds of the general Formula I increase metabolismin a significantly lower extent and for a shorter period of time thaneither amphetamine or 1-deprenyl.

II/6. Determination of the effect exerted on food intake, in rats

On well-fed satiated animals a 15 mg/kg p.o. or s.c. dose of thecompound according to Example 7 does not change food intake (amphetamineexhibits an anorectic effect already in a dose of 1 mg/kg). In a similardose it does not influence the food intake of rats fasted for 96 hours,which could be completely inhibited by a 2-5 mg/kg dose of amphetaminefor 3-4 hours.

A 5 mg/kg dose of the compounds according to Examples 4 and 13 give riseto a decreasing effect being approximately identical with that of about0.5 mg/kg of amphetamine, in the first hour.

II/7. Determination of ³ H-noradrenaine uptake in the nucleus freesupernatant of rat cortex (in vivo)

In cortex is homogenized in 0.32M saccharose with a teflon potter, thecell nucleus is sedimented by centrifuging at 0° C. with 1000 g for 20minutes; the supernatant thus obtained is used for the test. The intakeis accomplished in a Krebs-Heinseleit solution saturated with carbogen,in a final volume of 1 ml, at a ³ H-noradrenaline concentration of5.10¹⁸ moles. Pre-incubation and incubation are carried out at 37° C.for 5 minutes each. The reaction is stopped by adding 4 ml of ice-coldKrebs solution and the tissue is separated by GF/B filtration.Non-specific uptake is determined by using 10⁻⁴ M nisoxetine at 37° C.The radioactivity of the GF/B filter-paper is determined by liquidscintillation measurement in a toluene-PPO-POPOP-tritone mixture.

The results are summarized in Table 4.

                  Table 4                                                         ______________________________________                                        Compound              IC.sub.50 (M)                                           ______________________________________                                        DMI                   10.sup.-9 - 5 × 10.sup.-9                         Compound according to Example 4                                                                     5 × 10.sup.-8                                     Compound according to Example 6                                                                     5 × 10.sup.-7                                     Compound according to Example 14                                                                    1 × 10.sup.-7                                     1-deprenyl            7 × 10.sup.-6                                     ______________________________________                                    

Determination of the dopamineric activity increasing effect, on isolatedrat striatum preparations

Method: Kerecsen et al: Chromatography, the State of the Art,(Eds.Kalasz, Ettre) Akademiai Kiado Budapest (1985) page 195-203.

In ex vivo tests the animals are treated s.c. for 3 weeks and the organis removed 2 hours after administering the last injection.

The results are summarized in Tables 5 and 6.

                  TABLE 5                                                         ______________________________________                                        Change of the dopamine (DA) an DOPAC concentration                            of the bath of the organ, in vitro (pmole g.sup.-1 min .sup.-1)               Test compound                                                                             Dose        DA        DOPAC                                       ______________________________________                                        Control     --           91       258                                         Example 6   0.3         214.sup.x 172.sup.×                                         1.0         366.sup.x 190.sup.x                                               3.0         290.sup.x 331.sup.x                                               10.0        477.sup.x 537.sup.x                                   ______________________________________                                         .sup.x statistically significant                                         

                  TABLE 6                                                         ______________________________________                                        Change of the dopamine (DA) an DOPAC concentration of the                     bath of the organ, ex vivo (pmole g.sup.-1 min .sup.-1                        Test compound                                                                             Daily dose  DA        DOPAC                                       ______________________________________                                        Control     --           91       258                                         Example 7   0.25        257.sup.x 222                                                     5.0         189.sup.x 223                                         ______________________________________                                         .sup.x statisticaIIy significant                                         

II/8. Acute toxicity (on rats)

The results are summarized in Table 7.

                  TABLE 7                                                         ______________________________________                                        Test compound          LD.sub.50 mg/kg                                        Example No. i.v.       s.c.       p.o.                                        ______________________________________                                         1          --          135       --                                           2          50         >200 (%)   --                                           3          --           75 (0%).sup.x                                                                          --                                           4          27           50       270                                          5          --         >150 (0%)  --                                           6          40          140       300                                          7          --         >200 (0%)  --                                           8          46          195       --                                           9          --          160       --                                          10          18          175       --                                          11          --          110       --                                          12          16          >25.sup.x --                                          13          --          >50 (0%).sup.x                                                                          --                                          14          --         >200 (0%)  --                                          ______________________________________                                         .sup.x a more concentrated solution cannot be prepared.                  

II/9 Inhibition of the noradrenaline releasing effect of tyramine, on arabbit pulmonary artery preparation (in vitro)

Method: J. Knoll: J. Neurl. Transm. 43 177 (1978)

The test comprises the following steps:

1) Taking a control tyramine curve, in cumulative dosage (tyramine doses1, 3, 8, 18 ug/ml).

2) After washing for 20 minutes, a control tyramine curve is takenagain.

3) Equilibration with a single dose of the test compound of the FormulaI for 30 minutes.

4) Taking a tyramine curve in the presence of the test compounds, asdescribed in Par. 1).

5) After washing for 20 minutes, a tyramine curve is taken again. Theresults are summarized in Table 8.

                  TABLE 8                                                         ______________________________________                                        Test compound                                                                 Example No.      IC.sub.50 (M)                                                                            r.sup.2                                           ______________________________________                                        1                7.47 × 10.sup.-6                                                                   0.78                                              2                3.68 × 10.sup.-7                                                                   0.77                                              3                7.47 × 10.sup.-6                                                                   0.80                                              4                1.22 × 10.sup.-6                                                                   0.77                                              6                8.46 × 10.sup.-7                                                                   0.61                                              7                1.41 × 10.sup.-5                                                                   0.74                                              8                1.89 × 10.sup.-6                                                                   0.7                                               9                7.99 × 10.sup.-7                                                                   0.69                                              10               1.80 × 10.sup.-6                                                                   0.69                                              11               cannot be given                                              12               3.46 × 10.sup.-6                                                                   0.96                                              13               5.01 × 10.sup.-7                                                                   0.80                                              14               cannot be given                                              ______________________________________                                    

What we claim is:
 1. A compound of the Formula XII ##STR10## wherein R⁵stands for alkyl having 2-4 carbon atoms. 2.N-propyl-1-phenyl-2-pentylamine or an acid addition salt thereof. 3.N-propyl-1-phenyl-2-butylamine or an acid addition salt thereof. 4.N-propyl-1-phenyl-2-hexylamine or an acid addition salt thereof.